This invention relates to the use of synthetic phorboxaxole A in the treatment of cancer and to novel phorboxazole A derivatives that are useful as anti-cancer agents. In particular, the invention includes novel dehydrobromo and mixed methyl ketal derivatives having potent cytostatic and apoptotic effects against cancer cells, including human leukemia, breast cancer, prostate cancer and brain cancer cells. Novel phorboxazole derivative compounds of the invention inhibit migration of cancer cells through extracellular matrix, an activity required for tumor metastisis. In addition, the invention relates to methods of using synthetic phorboxaxole A and novel phorboxazole A derivatives of the present invention as therapeutic agents.
Phorboxazoles are natural products isolated from the Indian Ocean sponge Phorbas sp (Searle, et al., 1995, J. Am. Chem. Soc., 117, 8126-8131). They have exhibited potent cytostatic activity against a variety of human solid tumor cell lines (Searle, et al., 1996, J. Am. Chem. Soc., 118, 9422-9423). The precise phorboxazole mechanism of action is unknown, however, they do not act as microtubule-targeted antimitotics and appear to arrest cell cycle at S phase (Molinski, T. F., 1996, Tetrahedron Letters, 37, 7879-7880).
The use of phorboxazoles as anti-cancer agents is limited due to problems associated with isolating the compounds from their natural source. Many marine sponge-derived natural products are the result of biosynthesis by symbiotic microorganisms that may only be temporarily associated with the sponge and not amenable to laboratory culture. Furthermore, the supply of marine sponges, the natural source of phorboxazoles, is limited and subject to harvesting restrictions. Hence, a synthetic route to provide phorboxazoles and active anti-cancer phorboxazole derivatives is needed to exploit the potential of these therapeutic agents.
Synthetic routes to phorboxazole and phorboxazole derivatives are needed to allow investigation of structure-activity relationships and the scope of cellular responses with respect to these compounds. In particular, synthetic phorboxazole compounds are needed to elucidate and confirm the structure of phorboxazole compounds associated with therapeutic activities. Because phorboxazoles have not been fully characterized, confirmation of the proposed chemical structures is needed to usefully apply this technology. Useful structures for phorboxazole compounds can be confirmed by their synthetic production and analysis of the activities of the synthesized compounds.
Phorboxazole compounds are complex and difficult to synthesize. The first synthetic phorboxazole compound was produced as described in Forsyth et.al., 1988, J.Am. Chem. Soc. 120:5597. It has now been determined, as described in the Examples below, that a synthetic phorboxazole A, having the structure (I) shown below, is active as a cytotoxic agent. In addition, specific derivatives of the synthetic phorboxazole A also have demonstrated cytoxic activity. Specific derivatives of the synthetic phorboxazole A that may not be cytotoxic, are demonstrated in the Examples below to inhibit cell migration and invasion, and thus provide useful agents to prevent cancer cell metastases.
Synthetic phorboxazole A having the chemical structure (I) shown below and specific phorboxazole A derivatives were synthesized and examined for their cytotoxic effects on cancer cells, including human leukemia, breast cancer, prostate cancer and brain cancer cells. Synthetic phorboxazole A and novel dehydrobromo and mixed methyl ketal derivatives of phorboxazole A were found to exhibit potent cytotoxic activity against cancer cells at nanomolar concentrations.
Generally, the present invention relates to novel compounds and compositions having potent cytotoxic activity against cancer cells. One embodiment relates to compositions containing an effective cytotoxic or inhibitory amount of a synthetic phorboxazole A and of a novel dehydrobromo or mixed methyl ketal derivative of phorboxazole A. The cytotoxic compounds of the invention include those having the following formulae: 
Another embodiment of the present invention provides compositions formulated for delivery of the cytotoxic phorboxazole compounds to a subject as a pharmaceutical composition.
A further embodiment of the present invention provides methods to inhibit the growth or induce apoptosis of cancer cells, by administering to a subject or contacting cancer cells with an effective amount of a compound or composition of the present invention.
Yet another embodiment of the present invention provides specific derivatives of Phorboxazole A and methods to inhibit adhesion and migration of cancer cells through extracellular matrix, an activity required for tumor metastisis. The structures and activities of these compounds are described in the Examples below.
A further embodiment of the present invention provides a method for the synthesis of Phorboxazole A derivatives as described in the Examples below.
The above summary of the present invention is not intended to describe each disclosed embodiment or every implementation of the present invention. The Figures and the detailed description which follow more particularly exemplify these embodiments.